1. Diabetes Mellitus 101 for Cardiologists (and Alike): 2015 Stan Schwartz MD,FACP Affiliate, Main Line Health System Emeritus, Clinical Associate Professor of Medicine, U of Pa. 6105472000 An Aggressive Pathophysiologic Approach to Therapy of Type 2 Diabetes in Cardiometabolic Patients: Looking at Diabetes Medications with a Cardiologists Eye Part 13

2. Insulin Secretagogues: Sulfonylureas and “Glinides” Safety and Efficacy -Decreases HbA 1c approx 1–2%(sfu, repaglinide)(0.5- 1.0%,neteglanide) -Adverse events: Wt gain, sulfa allergy (sfu,rare),  -cell apoptosis (sfu) Main risk = hypoglycemia, inc ischemia risk(~50% less w/repaglinide,75% less with neteglanide) Increase Cancer vs Metformin Abnormal ischemia pre-conditioning SO WHY USE SOMETHING THAT DESTROYS BETA-CELLS THAT YOU’D LIKE TO SAVE Davies MJ. Curr Med Res Opin. 2002;18(Suppl 1):s22-30.

3. Sulfonylureas and Ischemic Pre- conditioning

4. Meta-Analysis: Cardiovascular Risk With Sulfonylurea Plus Metformin Rao AD, et al. Diabetes Care. 2008;31:1672-1678. 0.25 1.0 4.0 Relative Risk (95% CI) 1.04 (0.62-1.75) 1.86 (1.33-2.61) 0.96 (0.82-1.12) 1.38 (1.13-1.69) 2.24 (1.26-3.99) 1.86 (1.03-3.35) 1.52 (0.84-2.76) 1.43 (1.10-1.85) Bruno (1999) Olsson (2000) Johnson (2005) Koro (2005) Evans (2006) (A) Evans (2006) (B) Evans (2006) (C) Overall Results With Combination Therapy Increased composite cardiovascular risk end point (RR 1.43; 95% CI, 1.10-1.85) All-cause mortality alone – not significant Cardiovascular disease mortality alone – not significant Composite end point: cardiovascular hospitalization or mortality Relative risk: combination therapy vs. diet, metformin alone, or sulfonylurea alone RR = relative risk

5. Higher Mortality Is Associated With Greater Exposure to Sulfonylurea Simpson SH, et al. CMAJ. 2006;174:169-174. A retrospective, inception cohort study conducted in 5795 new users of oral glucose-lowering medications - Insulin or combination therapy were excluded - Mean age: 66.3 years - Mean follow-up: 4.6 years - Main outcomes: all-cause mortality, death from acute ischemic event There was a greater risk of death associated with higher daily doses and better adherence for patients who used glyburide (HR = 1.3; 95% CI, 1.2-1.4), but not metformin (HR = 0.8; 95% CI, 0.7-1.1) 0 1 2 Glyburide (n = 4138) Metformin (n = 1537) 1.32 1.29 0.92 0.96 0.84 41.5 (37.6) 53.4 (70.2) Daily Dose Hazard ratio Monotherapy group Deaths/1000 person-years Lower (higher) 0 1 2 Glyburide (n = 4138) Metformin (n = 1537) 1.55 1.34 1.33 1.10 1.09 0.98 49.0 (75.8) 37.7 (41.3) Poor (good) Adherence Hazard ratio Monotherapy group Deaths/1000 person-years Unadjusted Adjusted for age, sex, chronic disease score (CDS), and nitrate use Adjusted for age, sex, CDS, nitrate use, physician visits, and hospital admissions

6. MUST CONSIDER TOTAL COST- Incretin vs Sulfonylureas- not per/pill 1.ER Visits 2.Hospitalizations 3.Mortality 4.Under-recognized- hypoglycemic unawareness 5.Lifestyle Restrictions, diminished quality of life 6.Worry for Spouse, Friends, Co-workers 7.Fear of Hypoglycemic leads to inadequate Control 8.Severe Hypoglycemia Raises the Risk of Dementia 9.Increased cost of increased number SMBG testing And Given Apoptosis, death of beta-cells with SU, you’ll need expensive drugs anyway in 1-3 years- but now at disadvantage of having lost b-cell mass And 2 Part-D insurers now ask for prior auth for GLYBURIDE, ? SUs

7.  Decrease HbA 1c 0.5–1%  Decrease PPG,TG  Delay DM Adverse events: flatulence,treat hypoglycemia with glucose Decrease b-cell demand- - dec CV outcomes, STOP- NIDDM

8. Other Meds with ‘synergistic’ Glycemic and CV Benefit Colsevelam lipid benefit (Ranolazine) Decrease angina ( or equivalent) Decreases arrhythmia Improves diastolic dysfunction, thus-decreases edema of Pio-, Decreases HgA1c, FBS in glucose dependent fashion, no hypoglycemia

9. Colsevelam in Prediabetes Handelsman

10. Other Meds with ‘synergistic’ Glycemic and CV Benefit Colsevelam lipid benefit (Ranolazine) Decrease angina ( or equivalent) Decreases arrhythmia Improves diastolic dysfunction, thus-decreases edema of Pio-, Decreases HgA1c, FBS in glucose dependent fashion, no hypoglycemia

11. CHANGE FROM BASELINE IN HbA1c IN DIABETIC PATIENTS Modified from: Morrow et al. Circulation Suppl. 2008 (Abstract) 48 -0.8 -0.6 -0.4 -0.2 0 Ranolazine Months of Follow Up Change in HbA1c (%) Placebo P<0.001 N=770 N=535

12. CARISA: DOSE DEPENDENT EFFECT OF RANOLAZINE ON HbA1c AFTER 12 WEEKS. Chisholm and Belardinelli (2008). CVT unpubl data 0750 mg1000 mg -1.5 -1.0 -0.5 0 Ranolazine n=37 n=47 p=0.0028 p<0.0001 HbA1c (%) (change from baseline) n=47